Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients
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Tolaney-2015-Role of vascular den.pdf
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Author(s)
Tolaney, Sara M.
Boucher, Yves
Duda, Dan G.
Seano, Giorgio
Ancukiewicz, Marek
Barry, William T.
Goel, Shom
Lahdenrata, Johanna
Isakoff, Steven J.
Yeh, Eren D.
Date Issued
November 2015
Journal
Proceedings of the National Academy of Sciences of the United States of America
Publisher
National Academy of Sciences (U.S.)
Citation
Tolaney, Sara M., Yves Boucher, Dan G. Duda, John D. Martin, Giorgio Seano, Marek Ancukiewicz, William T. Barry, et al. “Role of Vascular Density and Normalization in Response to Neoadjuvant Bevacizumab and Chemotherapy in Breast Cancer Patients.” Proc Natl Acad Sci USA 112, no. 46 (November 2, 2015): 14325–14330. © 2015 National Academy of Sciences
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Final published version
Abstract
Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Chemical Engineering
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DOI of Published Version
https://doi.org/10.1073/pnas.1518808112
